Background: Theophylline has an anti-inflammatory action that may account for its clinical effectiveness in the reduction of inflammatory cells in the airways. Dendritic cells (DCs) are professional antigen-presenting cells, capable of priming naïve T cells, and play key roles in the activation of immune responses in asthma.
Objective: The purpose of this study was to investigate the effects of theophylline on human monocyte differentiation into DCs and whether this involved antagonism of adenosine receptors.
Methods: Peripheral human blood monocytes were cultured in the presence of granulocyte/macrophage-colony stimulating factor and IL-4 to induce DC differentiation. The cells were incubated with theophylline, KF17837 (a selective A2a receptor antagonist) and enprofylline (A2b receptor antagonist) and co-incubated with selective adenosine A1 and A2a receptor agonists, a phosphodiesterase inhibitor (rolipram) and adenosine deaminase (ADA) to determine their effects on DC differentiation. In addition, depletion of adenosine receptors by small interfering RNA (siRNA) was also examined.
Results: Monocytes differentiated into myeloid DCs in the culture system. The number of DCs was remarkably reduced by 60-70% when theophylline was administered at a therapeutic concentration. This effect was concentration-dependently exacerbated, was partly mediated by cellular apoptosis and was effectively reversed by the addition of the A1 agonists [2-chloro-N(6)-cyclopentyladenosin, N(6)-cyclohexyladenosine, and N-ethylcarboxamidoadenosine (NECA)] or the A2a agonist (CGS-21680, NECA). The depletion of the adenosine A1 receptor by siRNA and addition of ADA remarkably reduced DC differentiation. Meanwhile, both enprofylline and rolipram had little effect.
Conclusion: Our findings suggest that the adenosine A1 (and possibly coordinated with A2a) receptors contribute to DC differentiation and survival. These findings provide further evidence that theophylline has an anti-inflammatory action in bronchial asthma.